POS0307 IMPAIRED GLYCAEMIC CONTROL IS ASSOCIATED WITH INCREASED RISK OF PSORIATIC ARTHRITIS: MENDELIAN RANDOMISATION STUDY
Authors: S. S. Zhao, A. Barton, J. Bowes
Journal: Annals of the Rheumatic Diseases (2022)

Background Psoriatic arthritis (PsA) and psoriasis are both strongly associated with impaired glycaemic control and type 2 diabetes. The risk of developing type 2 diabetes is estimated to be ~40% higher in PsA compared to controls [1]. However, these observational findings are susceptible to bias from reverse causation: Insulin resistance and impaired glycaemic control are evident well over a decade before clinical onset of type 2 diabetes [2]. Therefore, whether impaired glycaemic control is a cause or consequence of PsA is unclear. Testing this hypothesis using traditional observational designs is challenging since longitudinal assessments of glycaemic control before PsA onset are often not available. Mendelian randomisation (MR) is an epidemiologic method that provides evidence about putative causal relationships between modifiable exposures and disease outcomes using genetic variants as instrumental variables. MR is less likely to be affected by confounding or reverse causation than conventional observational designs because genetic variants are randomly allocated at conception. Objectives To estimate the effect of genetically predicted glycaemic traits - glycated haemoglobin (HbA1c), 2-hour glucose after oral glucose challenge (2hG), fasting glucose (FG), and fasting insulin (FI) - on risk of PsA and psoriasis compared to controls using two-sample MR. Methods We selected 320 independent (r 2 &lt;0.001) genome-wide significant (p&lt;5x10 -8 ) variants as instruments for HbA1c from a UK biobank genome-wide association study (GWAS) of 344,182 individuals, and 14 variants for 2hG, 67 for FG and 38 for FI from up to 200,622 individuals from a MAGIC consortium meta-analysis that adjusted for body mass index. Genetic associations for PsA were obtained from a GWAS comprising 3,609 cases (majority fulfilling CASPAR criteria) and 9,192 controls. Psoriasis data were obtained from 5,278 cases (96% European, defined using ICD and phecodes) and 650,391 controls from the UK biobank, FinnGen and BioBank Japan [3]. We used the inverse-variance weighted method to combine effect estimates from each variant using fixed-effect meta-analysis. Results Genetically predicted HbA1c increased risk of PsA (OR 1.18 per standard deviation (6.7 mmol/mol) increase in HbA1c; 95%CI 1.02, 1.36). 2hG (OR 1.55 per SD (0.6 mmol/L) increase; 95%CI 1.26, 1.89) and FG (OR 1.73 per SD (1.6 mmol/L) increase; 95%CI 1.35, 2.21) similarly increased PsA risk (Figure 1). FI was not associated with PsA risk. 2hG was the only glycaemic trait significantly associated with psoriasis (OR 1.21; 95%CI 1.04, 1.40). Figure 1. Mendelian randomisation estimates of the effect of glycaemic traits on risk of psoriatic arthritis and psoriasis. Conclusion This study provides supportive genetic evidence that impaired glycaemic control increases risk of PsA. By contrast, estimates were smaller when comparing psoriasis against controls with confidence intervals including the null. Improving glycaemic control may reduce PsA risk, although further studies are required to confirm these findings and to compare PsA directly against cutaneous only psoriasis. References [1]Solomon et al. The Risk of Diabetes Among Patients with Rheumatoid Arthritis, Psoriatic Arthritis, and Psoriasis. Ann Rheum Dis 2010;69:21147-7. [2]Tabák et al. Prediabetes: A high-risk state for developing diabetes. Lancet 2012;379:2279-90. [3]Sakaue et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nature Genetics 2021;53:1415-24. Acknowledgements This work was supported by Versus Arthritis (grant number 21173, grant number 21754 and grant number 21755). Disclosure of Interests None declared